Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

Abstract

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHRs, LHCGRs and FSHRs. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub–nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub–nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHRs in human brain samples, where transcripts were co–localized in MALAT1–positive neurons. In addition, we show high expression for all three receptors in the ventricular region—with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. TSHRs were expressed specifically in tanycytes. In contrast, Fshrs were localized to NeuN–positive neurons in the granular layer of the dentate gyrus in murine and human brain—both are Alzheimer's disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer’s disease in midlife women

“…These results point to the frontal cortex, a brain region subserving higher order cognitive processes such as working memory and executive functions 31 , as a main site for gonadotropic action on AD risk. In vitro and ex vivo studies show that the frontal cortex is rich in FSHR and LHR in both rodent and human brain 22,32 , and both receptors are highly expressed in limbic cortex, an AD vulnerable region in turn. At post-mortem, FSHR expression is higher in frontal regions of AD patients as compared to controls 32 , further linking FSH to neurological harm.…”

“…In vitro and ex vivo studies show that the frontal cortex is rich in FSHR and LHR in both rodent and human brain 22,32 , and both receptors are highly expressed in limbic cortex, an AD vulnerable region in turn. At post-mortem, FSHR expression is higher in frontal regions of AD patients as compared to controls 32 , further linking FSH to neurological harm. In vivo neuroimaging work also identi es the frontal cortex as a site of early vulnerability to both Aβ deposition and GMV loss during the prodromal phase of AD 11,33 .…”